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Canagliflozin, Dapagliflozin, and Empagliflozin, glucagon-like peptide-1 receptor agonists, are indicated for managing type II diabetes. Although the genotoxicity profiles of these drugs are well-explored, limited information exists regarding the genotoxic potential of their impurities. In this investigation, the dimer impurities of Canagliflozin, Dapagliflozin, and Empagliflozin underwent both in silico and in vitro assessments for mutagenic potential. Tester strains of Salmonella typhimurium and Escherichia coli were subjected to the Ames test, utilizing concentrations of up to 1 µg per plate, with and without the presence of metabolic activation. Evaluation of micronucleus induction in TK6 cells was conducted through a micronucleus test, exploring concentrations up to 500 µg/mL, with or without the presence of exogenous metabolic activation. Under the specific test conditions, the dimer impurities of Canagliflozin, Dapagliflozin, and Empagliflozin showed no evidence of mutagenicity or clastrogenicity, establishing their in vitro classification as nonmutagenic. These findings align with negative in silico predictions from quantitative structure-activity relationship (QSAR) analyses for mutagenicity and genotoxicity of the dimer impurities. Collectively, these studies contribute clinically relevant safety information by confirming that the dimer impurities of Canagliflozin, Dapagliflozin, and Empagliflozin are nonmutagenic and nongenotoxic, emphasizing the consistency between in silico and in vitro data.
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Objectives: Antibiotics are the most commonly administered medications among pediatric patients. However most of the time, accurate dose administration to children becomes a problem due to the extremely bitter taste. Cefpodoxime proxetil (CP) and roxithromycin (ROX) are antibiotics often prescribed to the pediatric population and have a bitter taste. Marketed formulations of these drugs are dry suspension and/or tablets. The lyophilization method involves various steps and thus is time consuming and expensive. The objective of this study was to mask the bitter taste of CP and ROX without compromising the solubility and drug release profile compared to marketed formulations, as well as to overcome the disadvantages associated with the currently used lyophilization technique. Methods: Hot melt extrusion (HME) technology was used to process CP and ROX individually with Eudragit E PO polymer. The extrudates obtained were characterized by Fourier transform infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry. The powdered extrudates were formulated as dispersible tablets and evaluated for in vitro and in vivo taste-masking efficiency. Results: The tablets prepared in this study showed comparable dissolution profiles but the taste-masking efficiency was significantly enhanced compared to the marketed tablets of CP and ROX. The results of in vivo human taste-masking evaluation were also in agreement with the in vitro taste-masking studies. Conclusion: The current work presents solvent-free, scalable, and continuous HME technology for addressing the bitter taste issues of CP and ROX. The disadvantages associated with the currently used lyophilization technique were overcome by developing the formulations using HME technology.
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Background: There is a scarcity of studies evaluating the microbial profile, antimicrobial susceptibility, and prevalence of MDR/XDR pathogens causing medical device-associated infections (MDAIs). The present study was sought in this regard. Materials and methods: An ambispective-observational, site-specific, surveillance-based study was performed for a period of 2 years in the intensive care unit (ICU) and high dependency unit (HDU) (medicine/surgery) of a Tertiary-care University Hospital. Three commonly encountered MDAIs including central-line-associated bloodstream infections (CLABSI), catheter-associated urinary tract infections (CAUTI), and ventilator-associated pneumonia (VAP), were targeted. Results and conclusion: Of the total 90 patients, 46 (51.1%) were admitted to the ICU (medicine/surgery), and the remaining 44 (48.8%) were admitted to the HDU (medicine/surgery). The median (P25-P75) age of the total patients was 55 (43.1-62.3) years. Male 61 (67.8%) preponderance was observed. Sixty-two of 90 (68.9%) were immunocompromised. A total of 104 pathogens causing MDAIs were isolated. Staphylococcus epidermidis (CoNS), and Staphylococcus capitis were commonly isolated multi-drug resistant (MDR) gram-positive pathogens causing MDAIs. Similarly, carba-resistant Klebsiella pneumoniae, Stenotrophomonas maltophilia, and carba-resistant Acinetobacter baumanni were commonly isolated MDR gram-negative pathogens causing MDAIs. Five of 9 (55.5%) K. pneumoniae and three of 9 (33.3%) S. maltophilia isolates were found to be extensively drug resistant. Among Candida, C. parapsilosis was the most prevalent fungal pathogen causing CLABSI and CAUTI in patients admitted to ICU/HDU. How to cite this article: Suryawanshi VR, Pawar A, Purandare B, Vijayvargiya N, Sancheti S, Philip S, et al. Microbial Profile, Antimicrobial Susceptibility, and Prevalence of MDR/XDR Pathogens Causing Medical Device Associated Infections: A Single Center Study. Indian J Crit Care Med 2024;28(2):152-164.
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Boldine is an alkaloid obtained from the medicinal herb Peumus boldus (Mol.) (Chilean boldo tree; boldo) and belongs to the family Monimiaceae. It exhibits a wide range of pharmacological effects such as antioxidant, anticancer, hepatoprotective, neuroprotective, and anti-diabetic properties. There is a dearth of information regarding its pharmacokinetics and toxicity in addition to its potential pharmacological activity. Boldine belongs to the aporphine alkaloid class and possesses lipophilic properties which enable its efficient absorption and distribution throughout the body, including the central nervous system. It exhibits potent free radical scavenging activity, thereby reducing oxidative stress and preventing neuronal damage. Through a variety of neuroprotective mechanisms, including suppression of AChE and BuChE activity, blocking of connexin-43 hemichannels, pannexin 1 channel, reduction of NF-κß mediated interleukin release, and glutamate excitotoxicity which successfully reduces neuronal damage. These results point to its probable application in reducing neuroinflammation and oxidative stress in epilepsy, Alzheimer's disease (AD), and Parkinson's disease (PD). Moreover, its effects on serotonergic, dopaminergic, opioid, and cholinergic receptors were further investigated in order to determine its applicability for neurobehavioral dysfunctions. The article investigates the pharmacokinetics of boldine and reveals that it has a low oral bioavailability and a short half-life, requiring regular dosage to maintain therapeutic levels. The review studies boldine's potential therapeutic uses and mode of action while summarizing its neuroprotective benefits. Given the favorable results for boldine as a potential neurotherapeutic drug in laboratory animals, more research is required. However, in order to optimise its therapeutic potential, it must be more bioavailable with fewer detrimental side effects.
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Aporfinas , Doenças do Sistema Nervoso , Peumus , Animais , Cinética , Antioxidantes/farmacologia , Aporfinas/farmacologia , Aporfinas/uso terapêutico , Aporfinas/química , Peumus/químicaRESUMO
Docetaxel (DOC) is a potent anticancer molecule widely used to treat various cancers. However, its therapeutic efficacy as a potential anticancer agent has been limited owing to poor aqueous solubility, short circulation time, rapid reticuloendothelial system uptake, and high renal clearance, which consecutively showed poor bioavailability. In the present investigation, we developed polyethylene glycol (PEG) decorated solid lipid nanoparticles (SLN) using the solvent diffusion method to increase the biopharmaceutical properties of DOC. PEG monostearate (SA-PEG2000) was initially synthesized and characterized using various analytical techniques. Afterwards, DOC-loaded SLN was synthesized with and without SA-PEG2000and systematically characterized for in-vitro and in-vivo properties. Spherical-shaped SA-PEG2000-DOC SLN showed hydrodynamic diameter and zeta potential of 177 nm and -13 mV, respectively. During the in-vitro release study DOC-loaded SLN showed a controlledrelease of approximately 54.35 % ± 5.46 within 12 h with Higuchi release kinetics in the tumor microenvironment (pH 5.5).In an in-vitro cytotoxicity study,SA-PEG2000-DOC SLN showedsignificantlylower IC50values(p < 0.001)compared to DOC-SLN and DOC aloneagainst prostate cancer cell lines (PC-3). Similarly, an in-vitro cellular uptake study showed a significant increase in intracellular DOC concentration for SA-PEG2000-DOC SLN. Additionally, inin-vivostudies,PEGylated SLN of DOC showed around 2- and 15-fold increase in the maximum concentration of drug (Cmax) and area under the curve (AUC), respectively, as compared to plain DOC solution due to the uniquehydrophilicity and hydrophobicity balance and electrical neutrality of specially designed PEG architect. The biological half-life (t1/2) and mean residence time (MRT) was found to increase from 8.55 and 11.43 to 34.96 and 47.68 h, respectively, with SA-PEG2000-DOC SLN. Moreover, the bio-distribution study indicates high DOC concentration in the plasma which signifies the more pronounced blood residence time of SA-PEG2000-DOC SLN. In a nutshell, SA-PEG2000-DOC SLNwasfound to bea promising and efficient drug delivery platform for the management of Metastatic Prostate cancer.
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Nanopartículas , Neoplasias da Próstata , Masculino , Humanos , Docetaxel , Lipídeos/química , Nanopartículas/química , Neoplasias da Próstata/tratamento farmacológico , Polietilenoglicóis/química , Tamanho da Partícula , Microambiente TumoralRESUMO
PURPOSE: Aromatic turmerone, a major constituent of turmeric oil, has been recently reported for proliferation of neural stem cell showing great potential for effective treatment in neurodegenerative disorders. However, its effect as oral brain targeted formulation for neuroprotection has not yet reported. The objective of the study was to investigate the pharmacokinetic of curcumin loaded turmeric oil microemulsion for brain targeting and probing the protective effect against trimethyltin induced neurodegeneration in adult zebrafish. METHODS: Initially, in vivo plasma and brain pharmacokinetics was performed to determine improvement in relative bioavailability in rats followed by biodistribution and histopathological evaluation. Furthermore, the neuroprotective effect of the formulation was assessed in trimethyltin induced neurodegeneration model using adult zebrafish by behavioral analysis and biochemical analysis. RESULTS: The in vivo plasma and brain pharmacokinetics showed 2-fold and 1.87-fold improvement respectively. Biodistribution study revealed significantly lower concentration in organs other than brain. Furthermore, curcumin microemulsion exhibited improved spatial memory by remembering the training and made correct choices after curcumin microemulsion treatment than other treatment groups. Histopathological evaluation confirmed neuroprotective effect on zebrafish brains. The biochemical analysis revealed reduced oxidative stress in curcumin microemulsion treated group. CONCLUSIONS: Overall results showed a great potential of curcumin microemulsion for brain targeting in the effective treatment of neurological ailments.
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Curcumina , Fármacos Neuroprotetores , Ratos , Animais , Peixe-Zebra , Distribuição Tecidual , Curcuma , EncéfaloRESUMO
Drug absorption is improved by the intranasal route's wide surface area and avoidance of first-pass metabolism. For the treatment of central nervous system diseases such as migraine, intranasal administration delivers the medication to the brain. The study's purpose was to develop an in situ nasal hydrogel that contained liposomes that were loaded with sumatriptan succinate (SS). A thin-film hydration approach was used to create liposomes, and a 32 factorial design was used to optimize them. The optimized liposomes had a spherical shape, a 171.31 nm particle size, a high drug encapsulation efficiency of 83.54%, and an 8-h drug release of 86.11%. To achieve in situ gel formation, SS-loaded liposomes were added to the liquid gelling system of poloxamer-407, poloxamer-188, and sodium alginate. The final product was tested for mucoadhesive strength, viscosity, drug content, gelation temperature, and gelation time. Following intranasal delivery, in vivo pharmacokinetic investigations showed a significant therapeutic concentration of the medication in the brain with a Cmax value of 167 ± 78 ng/mL and an area under the curve value of 502 ± 63 ng/min·mL. For SS-loaded liposomal thermosensitive nasal hydrogel, significantly higher values of the nose-to-brain targeting parameters, that is, drug targeting index (2.61) and nose-to-brain drug direct transport (57.01%), confirmed drug targeting to the brain through the nasal route. Liposomes containing thermosensitive in situ hydrogel demonstrated potential for intranasal administration of SS.
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Lipossomos , Sumatriptana , Sumatriptana/farmacocinética , Hidrogéis/metabolismo , Poloxâmero/metabolismo , Encéfalo/metabolismoRESUMO
The mitochondria are a dynamic powerhouse organelle that contributes greatly to cancer therapy. Solving the current problems that occur mostly in chemotherapy and diagnosis of various cancers targeting the Mitochondria is an implying approach. In this review, it is discussed how the tethering of mitochondrial-targeting moieties to chemotherapeutics, fluorescent dyes and photothermal molecules can enhance the anticancer effect. The most extensively used mitochondrial targeting conjugate is Triphenyl phosphonium (TPP), which is a delocalized lipophilic cation that gets easily accumulated via the endocytosis mechanism due to the decreased mitochondrial membrane potential of the cancer cell. Credited for this characteristic, TPP has been extensively investigated in targeting mitochondria and delivery of cancer theranostics. This mitochondrial targeting strategy attracted great attention in cancer targeting nanotechnology. The TPP based nanoformulation have exhibited amplified therapeutic outcomes in the treatment of various cancer. Thus, TPP is an ultimate carrier with magnificent potential as a mitochondrial targeting agent.
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Mitocôndrias , Mitocôndrias/metabolismo , Cátions/metabolismoRESUMO
Background: The three-dimensional (3D) printing is paradigm shift in the healthcare sector. 3D printing is platform technologies in which complex products are developed with less number of additives. The easy development process gives edge over the conventional methods. Every individual needs specific dose treatment. 'One size fits all' is the current traditional approach that can shift to more individual specific in 3D printing. The present review aims to cover different perspectives regarding selection of drug, polymer and technological aspects for 3D printing. With respect to clinical practice, regulatory issue and industrial potential are also discussed in this paper. Main body: The individualization of medicines with patient centric dosage form will become reality in upcoming future. It provides individual's need of dose by considering genetic profile, physiology and diseased condition. The tailormade dosages with unique drug loading and release profile of different geometrical shapes and sizes can easily deliver therapeutic dose. The technology can fulfill growing demand of efficiency in the dose accuracy for the patient oriented sectors like pediatric, geriatric and also easy to comply with cGMP requirements of regulated market. The clinical practice can focus on prescribing each individual's necessity of dose. Conclusion: In the year 2015, FDA approved first 3D printed drug product, which is initiator in the new phase of manufacturing of pharmaceuticals. The tailormade formulations can be made in future for personalized medications. Regulatory approval from agencies can bring the 3DP product into the market. In the future, formulators can bring different sector-specific products for personalized need through 3DP pharmaceutical product.
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Intranasal route provides large surface area, avoids first-pass metabolism, and results in improved drug absorption. Intranasal delivery targets the drug to the brain for treatment of central nervous diseases viz migraine. The objective of the study was to formulate in situ nasal gel containing rizatriptan benzoate (RB)-loaded nanostructured lipid carriers (NLCs). NLCs were prepared by melt-emulsification ultrasonication method and optimized using 32 factorial design. Optimized NLCs were spherical with particle size of 189 nm, high drug encapsulation efficiency (84.5%), and 83.9% drug release at the end of 24 h. RB-loaded NLCs were incorporated into the liquid Carbopol 934P and Poloxamer 407 liquid gelling system to obtain in situ gel formation. The resultant product was assessed for gelling capacity, viscosity, and mucoadhesive strength. In vivo pharmacokinetic studies revealed significant therapeutic concentration of drug in the brain following intranasal administration with Cmax value of 5.1 ng/mL and area under the curve value of 829 ng/(min·mL). Significantly higher values of nose to brain targeting parameters, namely, drug targeting index (2.76) and nose to brain drug direct transport (63.69%) for RB-NLCs in situ nasal gel, confirmed drug targeting to brain through nasal route. The ex vivo nasal toxicity study showed no sign of toxicity to the nasal mucosa. Thus, the application of lipid carrier-loaded in situ gel proved potential for intranasal delivery of RB over the conventional gel formulations for efficient brain targeting.
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Portadores de Fármacos , Nanoestruturas , Encéfalo/metabolismo , Géis , Lipídeos , Triazóis , TriptaminasRESUMO
Methotrexate (MTX), a biopharmaceutical classification system-IV anticancer drug, exhibits low therapeutic efficacy. Moreover, its clinical applications were restricted due to its multidrug resistance (MDR) in cancer and its toxic effects. The present investigation was to fabricate 1, 2-dimyristoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium (DMPG-Na), (3ß)-cholest-5-en-3-ol (cholesterol) and calcium-based nanocochleates (NCs) as a potential oral delivery carrier for MTX to enhance its therapeutic efficacy with low toxicity. MTX-loaded NCs (MTX-NCs) was developed by the addition of calcium ion into preformed nanoliposomes (MTX-NLs) comprising MTX, DMPG-Na, with cholesterol and evaluated by in-vitro and in-vivo methods in comparison with MTX-NLs and pure MTX. Stable tubular rod structure of MTX-NCs possessing particle size, encapsulation efficiency and zeta potential of 374.1 ± 2.2 nm, 78.63 ± 2.12% and -71.2 mV, respectively were obtained from homogenous unilamellar, discrete and spherical structured MTX-NLs with a diameter and zeta potential of 363.3 ± 3.7 nm and -74.6 mV respectively. A thermal study revealed an amorphous state of MTX in MTX-NCs. Pharmacokinetics study in rats, MTX-NLs and MTX-NCs were showed controlled release with 5 and 6 fold improvements in oral bioavailability. Moreover, MTX-NCs showed low tissue distribution. These results collectively suggest that the developed system could be used to improve the therapeutic efficacy of MTX.
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Cálcio , Metotrexato , Ratos , Animais , Metotrexato/farmacologia , Metotrexato/química , Lipossomos , Fosfatidilgliceróis/química , Tamanho da Partícula , Colesterol/química , Excipientes , Portadores de Fármacos/químicaRESUMO
INTRODUCTION: Bioequivalence is established by comparing the bioequivalence study results of generic drugs with the reference listed drug. Several global regulatory agencies have published the guidance for locally acting orally inhaled drug products (OIDPs) for bioequivalence approaches. AREAS COVERED: The prime intent of the present article is to compare the regulatory guidance for bioequivalence assessment of locally acting OIDPs published by global regulatory authorities. Regulatory recommendations on bioequivalence were based on assessment for different parameters such as inhaler device, formulation, reference product selection, in-vitro, and in-vivo studies. The United States Food and Drug Administration and Health Canada suggest an aggregated weight of evidence approach and the European Medicines Agency promotes a stepwise approach, whereas though the Indian authorities have not published guidance specifically on OIDPs but provided guidelines for bioavailability and bioequivalence studies. EXPERT OPINION: For OIDPs, currently, there is no universally adopted methodology, and regulatory guidance has not been globally harmonized. By understanding and comparing bioequivalence recommendations for different regions, we can create more sensitive, and economic evaluation methods for OIDPs. This could open more alternatives of safe, effective generic OIDPs to the public.
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Preparações Farmacêuticas , Medicamentos Genéricos , Europa (Continente) , Índia , Equivalência Terapêutica , Estados Unidos , United States Food and Drug AdministrationRESUMO
This study aimed at carrying out a preformulation investigation of nanocochleates (NCs) and develop andrographolide-loaded nanocochleates. Preformulation study comprised of exploring the effect of trivalent and divalent ions on transition temperature (TT) of lipid (DMPG-Na), on particle size (PS), entrapment efficacy (EE), zeta potential (ZP) of NCs, and effect of NCs on change in lipid solubility post-NC formation. Further, the andrographolide-loaded nanocochleates made with CaCl2 (ANDNCs) were characterized for ZP, PS, EE, X-ray powder diffraction (PXRD), differential scanning calorimetry (DSC), transition electron microscopy (TEM), in vitro release studies, in vitro anticancer potential on the cell line of human breast cancer (MCF-7), in vivo oral pharmacokinetic studies, and tissue distribution in female Wistar rats. Nanocochleates developed with CaCl2 had a significant reduction in PS (1.78-fold) and ZP (1.38-fold), and elevation of EE (1.17-fold) as compared to AlCl3 developed NCs. Trivalent ions demonstrated elevation of TT as compared to divalent ions. Spiral-shaped ANDNCs demonstrated ZP, PS, and EE of - 121.46 ± 15.12 mV, 360 ± 47 nm, and 68.12 ± 3.81% respectively. In vitro release study of ANDNCs showed a strong pH-dependent release profile due to hydrogen bonding between NCs and andrographolide (AND). Formulated ANDNCs demonstrated 26.99-fold decrease in IC50 value as compared to free AND. Additionally, the oral bioavailability of AND from ANDNCs improved by 1.81-fold as compared to free AND. Furthermore, ANDNCs showed minimum accumulation within the vital organs such as liver, kidney, and spleen. Briefly, the preformulation study laid a platform for better understanding the NCs and its components. Further, developed ANDNCs revealed superior physiochemical properties to be used as an alternative for a clinical setting.
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Antineoplásicos/administração & dosagem , Diterpenos/administração & dosagem , Nanopartículas/química , Neoplasias/tratamento farmacológico , Fosfatidilgliceróis/química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Cátions , Diterpenos/farmacocinética , Diterpenos/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Feminino , Humanos , Tamanho da Partícula , Ratos , Ratos Wistar , Sódio , Solubilidade , Distribuição TecidualRESUMO
The present investigation aimed to develop curcumin loaded turmeric oil microemulsion for brain targeting. An effort has been made to investigate the role of functional components in developing brain targeted formulation which could enhance the bioavailability and uptake of drug in the brain upon oral administration. Preliminary studies like solubility study, emulsification study and construction of the pseudo ternary phase diagram were performed for screening components. The formulation was optimized by using extreme vertices mixture design. The optimized formulation was characterized for appearance, stability to centrifugation, dilution potential, globule size, zeta potential and drug content. Furthermore, ex-vivo permeation in chicken gut sac non everted technique and pharmacokinetic study in adult zebra fishes were carried out. The optimized formulation was found to clear, yellow-colored with the absence of phase separation and precipitation denoted the stability of formulation to centrifugation and dilution. The mean globule size, polydispersity index, zeta potential and drug content was observed as 29.13± 0.12 nm, 0.23 ± 0.01,-12.33 ± 1.37 mV and 99.10±3.91 %, respectively. Ex vivo permeation study revealed 2.41 fold enhancement in the steady-state flux when compared to curcumin solution. Furthermore, optimized formulation showed shorter Tmax (5 min) and higher AUC(0-∞) (7.93 µg/brain*min) compared to the curcumin solution which showed similar Tmax and AUC(0-∞) of 2.78 µg/brain*min after oral administration to zebra fishes revealing 3.97 fold enhancement. The results revealed enhanced ex vivo oral absorption and enhanced in vivo brain pharmacokinetics of curcumin via functional microemulsion in the zebra fish model.
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Curcumina , Administração Oral , Animais , Disponibilidade Biológica , Curcuma , Sistemas de Liberação de Medicamentos , Emulsões , Tamanho da Partícula , Solubilidade , Peixe-ZebraRESUMO
Polyurethanes (PUs) constitute an essential class of stimuli-responsive and biodegradable material, which has significantly contributed to the advancement of polymers utilization in the biomedical field. The bio-erodible PUs construct an active corridor for facilitating drug into tumor cells, which has significantly impacted the progression of nano-micellar delivery systems. The self-assembledcolloidal PUs pose distinctive features such as enhancing the solubility of hydrophobic chemotherapeutics, rapid cellular uptake, triggered erosion and drug release, bio-stimulus sensitivity, improvement in the targeting and proficiency ofbioactive. Cationic PUs can easily be condensed with genetic material to form polyplexes and have shown excellent transfection efficiency for potential gene therapy against various cancers. Their modifiable chemistry offers a tool to impart the desired multifunctionality such as biocompatibility, sensitivity to pH, redox, temperature, enzyme, etc. and ligand conjugation for active targeting. These diverse exceptional properties make them excellent nano-carrier for a variety of bioactive, including chemotherapeutic drugs, DNA, RNA, and diagnostic moieties to the target tissue or cells. The PUs based nano-devices have certainly uncovered the path to achieve ideal systems for controlled personalized therapy. The literature discussed in this review shed light on the research innovations carried out in the last ten years for the development of multifunctional PUs for triggered delivery of bioactive to treat various cancers.
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Neoplasias , Poliuretanos , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Micelas , Neoplasias/tratamento farmacológico , Polímeros/uso terapêuticoRESUMO
Methotrexate treatment has been associated with an array of liver-related adverse events like asymptomatic transaminase elevations, fatal necrosis and fibrosis. Here we present a child with relapse Pre B cell acute lymphoblastic leukaemia who developed and died of fulminant hepatic failure and pancytopenia soon after the administration of high-dose MTX. This case is unusual due to a series of adverse events that led to severe toxicity. The child received 1 g/m2 dose of methotrexate infusion for 36 hours. The patient developed drowsiness with altered sensorium in the 72 hours after starting the infusion. Investigations revealed severe pancytopenia along with grossly deranged liver function tests and coagulation profile. On the fourth day of paediatric intensive care unit admission, the child went into cardiac arrest and could not be revived.
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Falência Hepática Aguda/induzido quimicamente , Metotrexato/efeitos adversos , Pancitopenia/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Pré-Escolar , Relação Dose-Resposta a Droga , Evolução Fatal , Parada Cardíaca/etiologia , Humanos , Masculino , Metotrexato/administração & dosagemRESUMO
Methotrexate (MTX) is an extensively prescribed antimetabolite especially in the treatment of several pediatric cancers, though managing toxicities associated with methotrexate in high dose continues to be a challenge. A prospective study was carried out from April 2017 to October 2018. Children of either sex below 18 years at the time of enrolment and receiving high dose Methotrexate intravenous infusion over 24 h as a 2 g/m2, 3 g/m2 and 5 g/m2 dose was included in the study. The serum methotrexate level was estimated after the start of 48 h HDMTX infusion by using the ARCHITECT methotrexate assay. Toxicity due to HDMTX was assessed by Common Terminology Criteria for Adverse Events v.5.0. A total of 244 HDMTX infusions were delivered to 62 ALL patients. From the total of 244 cycles, serum methotrexate level in 35 cycles after the start of 48 h HDMTX infusion was found to be ≥ 1.0 µmol/L with reported toxicities among 31 cycles (88.6%). In 209 cycles MTX level was found to be less than 1.0 is statistically significant as compared to other cycles (p < 0.0001). Highest toxicities reported were in cycle I (38.8%). The toxicities such as oral mucositis, neutropenia, the elevation of liver enzymes, dermatological toxicities were found more in cycles whose methotrexate level are greater than 1.0 µmol/L. Dose reduction, increased the length of stay and treatment delay occurred in patients with severe toxicities. Severe toxicities of methotrexate can be interrelated with serum methotrexate levels at 48 h after the start of HDMTX infusion.
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Methotrexate is extensively used in the treatment of various malignancies and autoimmune conditions. Methotrexate is associated with several toxicities, while hypersensitivity reactions to methotrexate are unusual, but have been reported in adult cancer patients. Hereby, we detail the case of a child with acute lymphoblastic leukaemia who developed a hypersensitivity reaction to high-dose methotrexate infusion (HDMTX) during the fourth cycle of HDMTX. The child was rechallenged with another brand of methotrexate; she started complaining of itching on trunk within 5 min of infusion. Few studies have reported that desensitization has been helpful in children with hypersensitivity reactions allowing the continuation of HDMTX. However, it was decided to omit parenteral methotrexate for this child. Cranial radiotherapy was given for CNS prophylaxis. In conclusion, unexpected hypersensitivity with methotrexate should be kept in mind during the treatment especially with high-dose infusion.
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Antimetabólitos Antineoplásicos/efeitos adversos , Hipersensibilidade a Drogas/diagnóstico , Metotrexato/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antimetabólitos Antineoplásicos/administração & dosagem , Criança , Hipersensibilidade a Drogas/etiologia , Feminino , Humanos , Metotrexato/administração & dosagemRESUMO
The number of unit operations to be followed in the preparation of tablets was cumbersome and may introduce material as well as process-related critical parameters which may negatively affect the quality of final formulation. The hypothesis of the present research was to develop directly compressible, high-strength extended-release spherical agglomerates of talc containing indapamide by crystallo-co-agglomeration technique. Hydroxypropyl methylcellulose 15 cps and polyethylene glycol 6000 were used to impart the desired sphericity, strength, and deformability to agglomerates, respectively. Ethyl cellulose 10 cps was used to improve the strength of agglomerates and achieve extended release. Design of experiment (rotatable central composite design) was implemented for the elucidation of the effect of type and quantity of polymers on quality attributes of agglomerates. Prepared agglomerates were evaluated for morphological, micromeritic, mechanical, and drug release properties. A satisfactory yield (> 97%, wt/wt), better crushing strength, and low friability of agglomerates indicated good processing and handling characteristics. Compatibility and reduced crystallinity of indapamide in agglomerates were confirmed by spectroscopic and X-ray diffraction studies. Formation of the miniscular dosage form and hydrophobicity of talc were the key factors observed in controlling and extending the drug release (up to 6 h) from agglomerates. Hence, the developed crystallo-co-agglomeration technique could be successfully used for the preparation of directly compressible high-strength extended-release spherical agglomerates of indapamide.
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Química Farmacêutica/métodos , Desenho de Fármacos , Derivados da Hipromelose/síntese química , Talco/síntese química , Cristalização/métodos , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/farmacocinética , Derivados da Hipromelose/farmacocinética , Tamanho da Partícula , Polietilenoglicóis/síntese química , Polietilenoglicóis/farmacocinética , Comprimidos , Talco/farmacocinética , Difração de Raios X/métodosRESUMO
The present investigation is to study the effect of two different induction ports (IP), i.e., USP IP and USP-modified IP equipped with andersen cascade impactor on in vitro aerodynamic performance along with the impact of USP-modified glass sampling apparatus on delivered dose uniformity of fluticasone propionate (FP) dry powder inhaler (DPI). FP DPI was fabricated by spray drying technique using engineered mannitol microparticles (EMP) with different force controlling agents, i.e., leucine and magnesium stearate. Additionally, commercially available two DPI inhaler devices namely Handihaler® and Breezhaler® were used to aerosolize the FP blends. Spherical smooth surface of EMP showed good powder flow properties and acceptable percentage content uniformity (> 95%). Amounts of FP deposited in cascade assembly using USP-modified IP with the Breezhaler® device was significantly higher (1.32-fold) as compared with the Handihaler® device. Moreover, USP-modified IP showed better deposition as compared with USP IP. Additionally, both inhaler devices showed a satisfactory delivered dose (> 105%) for FP using modified glass sampling apparatus at a flow rate of 60 L/min for 2 s. It was interesting to note that not only formulation properties but also IP geometry and device resistance have significant impact on DPI deposition pattern. This study is a first detailed account of aerodynamic performance of FP using USP-modified IP and USP-modified glass sampling apparatus. Thus, it can be of potential importance for both the academic and industry perspective.